Project summary Recently, we characterized a natural regulatory T cell (nTreg) lineage that recognizes the heavy constant region of immunoglobulin (Fc) very important in down-sizing the inflammation. Fc-specific nTreg can be found in circulation in healthy donors but not in Kawasaki disease (KD) patients before high doses of intravenous immunoglobulin (IVIG) therapy or in Rheumatoid Arthritis patients. KD is a self-limited, T cell-mediated acute vasculitis that is the most common cause of acquired pediatric heart disease. Coronary artery abnormalities (CAA) occur in up to 25% of untreated children but can be largely prevented by timely administration of IVIG. We showed that damage to the arterial wall was associated with failure to expand the Fc-specific nTreg population after IVIG, hence establishing an inverse correlation between the numbers of Fc-specific nTreg and CAA. Notably, Fc-specific nTreg were undetectable in all acute KD patients prior to IVIG and in adult patients who had a remote history of KD in childhood. Following IVIG administration, KD patients with normal coronary arteries have detectable Fc-specific nTreg in the circulation, but patients with CAA+ do not. Thus, the expansion of Fc-specific nTreg appears to play a hitherto unappreciated protective role in vasculitis and is a new mechanism of action of IVIG. Preliminary studies in healthy donors and RA patients indicate that immunodominant Fc peptides can be identified and include pan-HLA binders. In RA, the nTreg response to the whole Fc protein was low or absent similar to KD children who develop CAA despite IVIG therapy. This study will define the molecular basis of Fc-specific nTreg recognition and a possible defect in the antigen processing of the endogeneous Fc presented by IgG+ B cells in KD children who develop CAA. The proposed experiments will reveal the immunodominant minimal peptide epitopes of the Fc recognized by the nTreg in 70 KD patients after IVIG therapy, will unveil the immunodominant peptides endogenously presented by IgG+ B cells to nTreg, and will evaluate the nTreg potency in down-regulating pro-inflammatory T cells. The study will characterize the nTreg population in infants and young children for whom the immune regulation is critical during the selection of T cell responses to the neoantigens that they encounter after birth without experiencing undue inflammation. Thus, the study will have implications for control of inflammation beyond KD as a disease model. Down-regulations of inflammation induced by immunomodulatory peptides recognized by nTreg may later be developed as a novel anti-inflammatory therapy not only for KD children, but with a broader application to autoimmune diseases including RA, and neurological diseases, including Alzheimer's, multiple sclerosis and narcolepsy where IVIG has been proven successful.